dc.contributor.author |
McDermott MS |
|
dc.contributor.author |
Chumanevich AA |
|
dc.contributor.author |
Lim CU |
|
dc.contributor.author |
Liang J |
|
dc.contributor.author |
Chen M |
|
dc.contributor.author |
Altilia S |
|
dc.contributor.author |
Oliver D |
|
dc.contributor.author |
Rae JM |
|
dc.contributor.author |
Shtutman M |
|
dc.contributor.author |
Kiaris H |
|
dc.contributor.author |
Győrffy, Balázs |
|
dc.contributor.author |
Roninson IB |
|
dc.contributor.author |
Broude EV |
|
dc.date.accessioned |
2017-03-29T08:09:20Z |
|
dc.date.available |
2017-03-29T08:09:20Z |
|
dc.date.issued |
2017 |
|
dc.identifier.citation |
pagination=12558-12575;
journalVolume=8;
journalIssueNumber=8;
journalTitle=ONCOTARGET; |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/4125 |
|
dc.identifier.uri |
doi:10.18632/oncotarget.14894 |
|
dc.description.abstract |
Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERalpha expression, suggesting that CDK8 could be functionally associated with ER. We have found that CDK8 inhibition by CDK8/19-selective small-molecule kinase inhibitors, by shRNA knockdown or by CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells; this effect was exerted downstream of ER. Estrogen addition stimulated the binding of CDK8 to the ER-responsive GREB1 gene promoter and CDK8/19 inhibition reduced estrogen-stimulated association of an elongation-competent phosphorylated form of RNA Polymerase II with GREB1. CDK8/19 inhibitors abrogated the mitogenic effect of estrogen on ER-positive cells and potentiated the growth-inhibitory effects of ER antagonist fulvestrant. Treatment of estrogen-deprived ER-positive breast cancer cells with CDK8/19 inhibitors strongly impeded the development of estrogen independence. In vivo treatment with a CDK8/19 inhibitor Senexin B suppressed tumor growth and augmented the effects of fulvestrant in ER-positive breast cancer xenografts. These results identify CDK8 as a novel downstream mediator of ER and suggest the utility of CDK8 inhibitors for ER-positive breast cancer therapy. |
|
dc.relation.ispartof |
urn:issn:1949-2553 |
|
dc.title |
Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer |
|
dc.type |
Journal Article |
|
dc.date.updated |
2017-03-17T11:56:50Z |
|
dc.language.rfc3066 |
en |
|
dc.identifier.mtmt |
3197021 |
|
dc.identifier.pubmed |
28147342 |
|
dc.contributor.department |
SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika |
|
dc.contributor.institution |
Semmelweis Egyetem |
|
dc.mtmt.swordnote |
FELTÖLTŐ: Sonnevend Kinga - sonnevend.kinga@med.semmelweis-univ.hu |
|